We seek to determine whether there is a genetic predisposition for the development of asparaginase-related pancreatitis. Asparaginase is a highly effective drug in the treatment of childhood acute lymphoblastic leukemia (ALL), but is associated with significant side effects in up to one-third of patients. Patients who are unable to receive all of their intended doses of asparaginase have a higher relapse rate than those who are able to tolerate all or nearly all of their doses, with a 5-year event-free survival rate of 73% for asparaginase-intolerant and 90% for asparaginase-tolerant patients (p<0.01). The most common cause of asparaginase intolerance is pancreatitis. The mechanism of asparaginase-induced pancreatitis is unknown. Recent studies suggest that genetic factors predispose to several types of pancreatitis, including chronic idiopathic and alcohol-induced pancreatitis. Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been associated with pancreatitis in people without cystic fibrosis. We hypothesize that children with ALL who have germline mutations of CFTR might be at increased risk for the development of asparaginase-related pancreatitis. The proposed investigations bring together two groups, one with expertise in asparaginase and the treatment of ALL and the other with expertise in the analysis of CFTR gene mutations/variations, in order to determine whether there is a pharmacogenetic relationship between CFTR gene mutations and the development of asparaginase-related pancreatitis. The frequency of CFTR gene mutations will be compared in children with ALL who had asparaginase-related pancreatitis and similarly treated children who did not. The finding of an association between asparaginase-related pancreatitis and CFTR gene mutations would make an important contribution to the understanding of the pathophysiology of drug-related pancreatitis. Additionally, because potential therapeutic interventions for CFTR-mediated pancreatitis are becoming available, the finding of an association might also lead to effective therapy for this currently untreatable form of pancreatitis. Prevention or treatment of asparaginase-induced pancreatitis could result in more children receiving all of their intended doses of asparaginase, potentially both reducing toxicity and enhancing efficacy of treatment for children with ALL.